The present invention relates to compositions formulated for administration to an eye. More specifically, the present invention relates to compositions formulated and administered to a human eye to improve vision, such as to reduce excessive pupil dilation in a reduced light including absent lighting conditions.
While it is generally known that pupil size varies in its diameter in a reduced light between individuals from 3 mm to 9 mm, little attention has been paid to the effect of this difference on vision, such as on night vision, vision in dim light and the like. However, individuals with large pupils suffer from much more light scatter, glare, halo, and related aberrant focus of light rays that can make function under certain conditions of lighting very difficult as disclosed in U.S. Pat. No. 6,515,006. This is due to the fact that the eye must focus through as much as nine times more corneal surface area in dim light conditions as compared to bright light conditions.
As the corneal curvature becomes increasingly imperfect as a function of distance from the corneal center, a greater degree of undesirable light scattering occurs the larger the corneal surface area is through which light is allowed to focus. This is particularly relevant to night vision and vision in any dimly lit environment, where the ideal surface area required for sufficient light entry is far exceeded due to genetic factors related to the light reflex common to many individuals. It therefore is desirable to minimize this excessive pupil response to a reduced light in such individuals.
The pupillary dilation that occurs in a reduced light including complete darkness allows increased light to enter the eye. However, a pupil size of about 3 mm to about 4 mm is the maximum size needed for this purpose, allowing 9 to 16 times more light to enter as compared to a 1 mm pupil in bright illumination. The mean pupil size in several studies of normal populations has been shown to be much larger, namely, about 6.1 mm. More recent studies using recently available technology for mapping optical imperfections known as higher order aberrations (HOA's, such as spherical aberration, coma, secondary astigmatism, trefoil, and the like) demonstrate a strong correlation between the increase in pupil size in darkness above 4 mm and the degree of HOA's to which the eye is exposed.
Further, individuals with increased optical refractive error, individuals with only partial correction of their refractive error, such as soft contact lens wearers with uncorrected astigmatism, individuals with excessive higher order aberrations, and individuals with previous refractive surgery with optical zones much smaller than their mesopic or scotopic pupil, refractive surgery with other induced higher order aberrations, and the like have still greater reduction in their quality of vision and/or contrast sensitivity (e.g., visual acuity in a reduced light), and an even more dramatic need for a reduced pupil light reflex response to reduced illumination. Laser vision correction in particular has added new quality of vision difficulties for many of these individuals. Exposing the retina to light focusing from as much as nine times more surface area than is necessary essentially magnifies every variation in curvature from the ideal. For example, a normal healthy population of individuals selected only for nearsightedness and/or astigmatism demonstrates over a 20% incidence of difficulty with night vision and night driving, as documented by the FDA for approval of recent laser vision correction machines.
In general, direct acting miotic agents, such as pilocarpine, have been used in an effort to decrease pupil size. However, pilocarpine causes brow ache, ciliary muscle contraction and pseudo myopia, excessive dimness when first applied since the pupil size is usually reduced to less than 2 mm, and redness. Its miotic effect is believed to last only a few hours, and it has a known, though remote, risk of retinal detachment. This is probably related to the pull on the retina from stimulated ciliary muscle contraction. In addition to pilocarpine, the use of certain sulfamoyl-substituted phenethylamine derivatives to reverse drug-induced mydriasis (e.g., dilation of the pupil caused by the administration of a drug) are disclosed in U.S. Pat. No. 5,288,759.
In general, alpha 1 antagonists are known to have propensity to reverse pupillary dilation with cyloplegic agents, and hence it might be inferred reduce the pupil light reflex. But, at the same time, the alpha 1 antagonists are by their intrinsic nature known to cause dilation of conjunctival and/or scleral vessels. This can cause undesirable redness to the eye. Of these, phentolamine has been demonstrated to have one of the best profiles with respect to pupil light reflex reduction and minimal induction of vascular dilation, and thus is useful for the purpose of reducing the pupil light reflex when applied as in topical eye medication disclosed in U.S. Pat. No. 6,515,006.
Another medication used to reverse pupillary dilation and studied for its effect on pupil size is dapiprazole, an alpha 1 adrenergic receptor blocking agent. Dapiprazole is 5,6,7,8 tetrahydro-3-[2-(4-o,tolyl-1-piperazinyl)ethyl]-8-triazolo[4,3-a]pyridine hydrochloride. In general, it is available in a 0.5% solution to partially counteract, or reverse, the dilation effect of phenylephrine, an adrenergic dilating agent, and the dilating and accommodation loss caused by tropicamide. However, dapiprozole is known to produce substantial increased redness and conjunctival chemosis (e.g., swelling) upon instillation. Further, it has been demonstrated that dapiprazole is not as effective with respect to reducing pupil size in dim light in clinical application as compared to, for example, phentolamine and phenoxybenzamine as disclosed in U.S. Pat. No. 6,515,006 when used topically for this purpose. Because of its side effects the commercial use of dapiprazole is indicated for sporadic use, such as the reversal of iatrogenic mydriasis, and not for repeat, regular, or chronic use.
In general, the receptors that mediate pupil dilation are located within the smooth muscle of the iris and are commonly referred to as adrenergic receptors. The adrenergic receptors can be further classified as alpha 1 or alpha 2 receptors. In the iris dilator muscle, adrenergic receptors that mediate pupil dilation are alpha 1 receptors. This classification can be further subdivided into alpha 1 receptor types specific to smooth muscle (which can vary for different organ systems), and frequently different receptor alpha 1 subclassification for vascular alpha 1 adrenergic receptors.
In the human bladder, for example, alpha 1a receptors mediate bladder contraction, while alpha 1b receptors are present in vascular tissue. Tamsulosin represents a somewhat preferential alpha 1a selective antagonist, which when administered orally reduces bladder spasm with a reduced effect on blood pressure as compared to known medications that include nonselective alpha antagonists. In addition to tamsulosin, other compounds or agents, such as KMD 3213, WB-4101, and 5-methyl urapidil, have an even greater specificity for alpha 1a selectivity. For example, KMD 3213 is being studied clinically to treat bladder spasticity due to its reduced effect on vascular tissue and lower incidence of hypotension (low blood pressure) than found with nonselective alpha 1a antagonists that have been used (such as doxazosin).
A need therefore exists to provide improved ophthalmic compositions that can effectively modulate the pupil light reflex in a reduced light to a more optimal range limit of dilation, to eliminate extraneous light and eliminate higher order aberrations in such lighting, thereby enhancing vision and to do so without inducing vascular effects in the eye, such as redness.